Figure 1.

Homocysteine metabolism: methionine – folate cycle and the folate shuttle Hcy is an intermediate metabolic product of methionine metabolism. Once methionine
is demethylated, producing Hcy it can be further catabolized to cystathionine and
cysteine via the transsulfuration pathway. This transsulfuration pathway is dependent
on the cystathionine beta synthase enzyme (CBS) and vitamin B6. Human vascular cells lack the CBS enzyme and therefore the transsulfuration pathway
is not present. In the remethylation cycle termed the Methionine – Folate Cycle, folic
acid (folate) serves as the methyl donor to convert Hcy to Methionine. This reaction
is dependent on the Methionine Synthase (MS) enzyme and the cofactor vitamin B12. Folate serves not only as a methyl donor but also as hydrogen and an electron donor.
This hydrogen and electron donation capability renders folate as a dual source for
stabilization of the tetrahydrobiopterin (BH4) Cofactor of the endothelial nitric oxide synthase (eNOS) reaction producing the
quintessential endothelial nitric oxide (eNO) and the additional function of being
a local endothelial microenvironment antioxidant. These findings have led to the hypothesis
of a Folate Shuttle phenomenon. As can be seen there may exist a relative endogenous
endothelial folate deficiency resulting in a toxic effect of Hcy accumulation within
endothelial cells as a result of this Folate Shuttle.